FcRn: The Architect Behind the Immune and Nonimmune Functions of IgG and Albumin

Abstract

The neonatal FcR (FcRn) belongs to the extensive and functionally divergent family of MHC molecules. Contrary to classical MHC family members, FcRn possesses little diversity and is unable to present Ags. Instead, through its capacity to bind IgG and albumin with high affinity at low pH, it regulates the serum half-lives of both of these proteins. In addition, FcRn plays an important role in immunity at mucosal and systemic sites through its ability to affect the lifespan of IgG, as well as its participation in innate and adaptive immune responses. Although the details of its biology are still emerging, the ability of FcRn to rescue albumin and IgG from early degradation represents an attractive approach to alter the plasma half-life of pharmaceuticals. We review some of the most novel aspects of FcRn biology, immune as well as nonimmune, and provide some examples of FcRn-based therapies.

Figure 1

A) Transport of IgG across the placenta in humans or fetal yolk sac of rabbits. In the endoderm of the fetal yolk sac IgG is internalized by fluid-phase endocytosis and encounters FcRn in early endosome; B) Transport of IgG across the intestine in rodents or ruminants. In new-born rats IgG is taken up by fluid-phase endocytosis or through binding to FcRn at the apical cell surface of enterocytes. This enables active FcRn-mediated transport of IgG across the cell and its subsequent release on the opposite, extracellular side at neutral pH. In such circumstances, FcRn transcytosis exhibits a dominant vector of transport from apical-to-basolateral directions which likely reflects concentration and pH gradients as well as cell-dependent factors; C) The catabolism of IgG (and potentially albumin) by FcRn in endothelial cells or hemaotpoietic cells (not shown here). Serum IgG is internalized by fluid-phase endocytosis and binds to FcRn in an acidic endosomal compartment. FcRn then recycles IgG back into neutral pH milieu of the circulation, thus extending its serum half-life. IgG not bound to FcRn due to levels that exceed FcRn capacity or other serum proteins are destined for lysosomal degradation.

Figure 2

A) In the adult human gut, both enterocytes and antigen-presenting cells (APCs) in the lamina propria express FcRn. Enterocytes transcytose IgG into the gut lumen where it binds to antigens. The IgG–immune complexes (IC, IgG-IC) are then delivered to dendritic cells (DC) in the lamina propria. Antigen-loaded DCs then migrate to the draining lymph nodes to prime T-cell responses. B) The IgG-IC can bind to FcγR on the surface of DC at neutral pH, initiating receptor-mediated endocytosis. This delivers the IgG-IC into the endolysosomal compartments. As these vesicles mature they become more acidic. Acidification allows IgG-IC to dissociate from FcγR and favours binding to FcRn. Such a “hand-off” enables efficient trafficking of the IgG-IC and the delivery of antigen into antigen processing pathways that promote the loading onto MHC class I and MHC class II molecules. Ligation of FcRn by IgG-IC also induces the production of IL-12 by the DC. The peptide loaded MHC molecules derived from IgG-IC, are then able to prime CD8⁺ and CD4⁺ T cells. While the secreted IL-12 acts upon the primed CD4⁺ T cells to induce T_H1 polarization, upon CD8⁺ T cells it promotes activation, cytotoxicity and a T_C1 phenotype. For simplification, although a monomeric IgG immune complex is shown in panels A and B, multimeric IgG-IC are the types responsible for antigen processing and induction of IL-12 secretion.